There are only two types of molecules that can recognize antigens in a specific manner. One is immunoglobulin or antibody and the other is T cell receptor (TCR), which is α/β or γ/δ heterodimeric glycoprotein on cell membrane. TCR heterodimers consist of α and β chains in 95% T cells, while in 5% T cells, TCR consists of γ and δ chains. Natural αβ hetero-dimeric TCRs have α-chain and β-chain, and α-chain and β-chain form subunit of αβ heterodimeric TCR. Generally, α and β chains of TCR are considered to have two “domains”, that is, TCRα chain variable domain (Vα) and TCRα chain constant domain (Cα), and TCRβ chain variable domain (Vβ) and TCRβ chain constant domain (Cβ).
TCR is the only receptor for presenting specific peptide antigens in Major Histocompatibility Complex (MHC). The exogenous or endogenous peptides may be the only sign of abnormality in a cell. In the immune system, once antigen-specific TCRs bind with pMHC complexes, it causes direct physical contact of a T-cell and an antigen presenting cell (APC). Then, the interaction of other membrane molecules in T cell and APC occurs and the subsequent cell signaling and other physiological responses are initiated so that a range of different antigen-specific T cells exert immune effects on their targets. Therefore, TCR is essential for the cellular immune function of the immune system.
Just like an immunoglobulin (antibody) which can be used as an antigen recognition molecule, TCR can be developed for diagnostic and therapeutic applications. There are many applications for soluble TCRs, which can be not only used in study of interaction of TCR-pMHC but also as a diagnostic tool for detecting infection or as a marker for autoimmune disease. Similarly, soluble TCRs can be used to deliver a therapeutic agent, such as a cytotoxic compound or an immunostimulatory compound, to cells presenting specific antigens or to inhibit T cells (e.g., the T cells which react with autoimmune peptide antigens). Furthermore, soluble TCRs can bind to other molecules (e.g., anti-CD3 antibodies) and re-direct T cells, so as to target and kill cells which present specific antigens.
Naturally occurring TCR is a membrane protein which is stabilized by its transmembrane region. For obtaining a soluble TCR protein, it is very difficult to obtain a soluble and stable TCR maintaining the ability to bind to its original ligand (i.e., pMHC) (Shin, et al., (1993) science 259: 1901). Instability and low protein yield are major obstacles for using TCRs or fragments thereof in the development of therapeutic or diagnostic agents. Some literatures describe a truncated form of TCR that only contains extracellular region or extracellular and cytoplasmic regions. Although such TCRs can be recognized by TCR-specific antibodies, the yield is low and when at a low concentration, can not identify MHC-peptide complex, indicating that it is easily denatured, and not stable enough. A skilled person in the art is making effort to develop soluble, stable T cell receptors.